Leukotriene antagonists for use in the treatment or inhibition of oral squamous cell carcinoma

ABSTRACT

This invention provides methods for the treatment or inhibitor of oral squamous cell carcinoma which comprises administering to a mammal in need thereof an effective amount of a compound having activity as a leukotriene B4 antagonist.

This application claims the benefit of U.S. Provisional Application Nos.60/034,269, filed Dec. 13, 1996 and 60/040,874 filed Mar. 21, 1997

BACKGROUND OF THE INVENTION

Squamous cell carcinoma is the most common malignant neoplasm of thehead and neck. It constitutes at least 75% of head and neck cancer inwhich patients show a high incidence of immunologic deficiencies andinflammatory symptoms. Despite improvements in the treatment modalitiesover the past 40 years, the 5-year survival rate of approximately 30%has not changed in the same period.

Oral squamous cell carcinoma has been linked to excessive cigarettesmoking and alcohol abuse, both individually and in combination. Otherfactors associated with oral cancer include poor dental hygiene andmalfitting dentures or broken teeth that cause chronic mucosalirritation. Occupational hazards include chronic dust exposure amongwoodworkers, which has been associated with cancer of the nasopharynx,and exposure to nickel compounds, which increases the risk of paranasalsinus cancers.

Epstein-Barr virus (EBV), the etiologic agent of infectiousmononucleosis, has been associated with nasopharyngeal carcinoma. Otherviruses have also been implicated, including oral herpes simplex virustype 1 and endogenous oncornaviruses.

Radiation exposure, as well as dietary deficiencies, may also predisposepersons to head and neck cancers.

About 90% of oral cancers are detected in only a few high-risk sites;the floor of the mouth, the ventrolateral aspect of the tongue, and thesoft palate complex. Buccal and labial vestibular carcinoma should beconsidered in people who use smokeless tobacco.

Cancer of the head and neck occurs in four major anatomic sites: theoral cavity, pharynx, larynx, and nasal and paranasal sinuses. Thesesites are subdivided into various component regions. The most commonsites of disease are the oral cavity and the oropharynx, which accountfor slightly less than 50% of cases, followed by the larynx, whichaccounts for about 30% of cases.

Early, asymptomatic oral cancer appears most often as a red(erythroplastic) lesion. Squamous cell carcinoma, not diagnosed in itsearliest stages appears later as a deep ulcer with smooth, indurated,rolled margins, fixed to deeper tissues. Biopsy is necessary to diagnosecarcinoma.

Squamous cell carcinomas are often diagnosed early because such cancerslead to local symptoms such as pain, hoarseness, and difficulty inswallowing. In many cases, however, diagnosis is delayed because localsymptoms or pain from nerve involvement does not occur until a largeprimary tumor develops. In such cases, regional nodal metastases may bethe initial manifestation. Distant metastases rarely occur withoutlocally advanced primary disease or nodal involvement.

Head and neck cancer may be a panmucosal disease of the upperaerodigestive tract; additional silent synchronous primary lesions occurfrequently. Patients with such a clinical picture are predisposed toadditional primary head and neck cancers at a later date (the incidenceis approximately three to five percent a year).

Although there are few tumor markers for head and neck cancer, the serumferritin level is reported to accurately reflect the stage and course ofdisease. (Ferritin is a major iron-storage protein of human tissues andis found in small quantities in the serum.) However, an elevated serumferritin level is not specific for head and neck cancer; its level isalso elevated in other cancers and in nonmalignant conditions.

Levels of antibodies to EBV in both established and occultnasopharyngeal carcinoma may be used as a diagnostic tool. Measurementsof IgA antibodies to viral capsid antigen (anti-VCA) and of IgGantibodies to early antigen (anti-EA) are the most specific tests,particularly for the undifferentiated types of Nasopharyngeal Carcinoma(NPC).

Cancers of the head and neck are staged according to the TNM system ofthe American Joint Committee on Cancer. The classification of theprimary tumor (T) varies depending on its site, size, and extent ofinvasion of and attachment to the surrounding tissues; only tumors ofthe oral cavity and oropharynx are classified using the same criteria.When the lesion cannot be measured accurately, the number of sitesinvolved is used to determine the T stage. Cervical lymph nodes (N) areclassified by the size, number, and distribution (homolateral orbilateral) of affected nodes. Disease is also classified by the presenceor absence of distant metastases (M). The overall stage of the diseaseis determined from the TNM stage: stage I and stage II diseases, whichare considered limited diseases, are accurately assessed by clinicalevaluation; stage III, or locally advanced, disease mainly includeslarger primary tumors with or without regional nodal spread (T₃ N₀, T₁₋₃N₁); and stage IV disease consists of either massive, extensivelyinvasive primary lesions with variable patterns of nodal involvement(T₁₋₄ N₂₋₃, T₄ N₀₋₁, or locally advanced disease) or any other TNcombination with distant metastases (M₁, or metastatic disease).

Although surgery and radiotherapy remain the mainstays of treatment,chemotherapy is playing an increasingly important role in the managementof this disease. Chemotherapy is used for palliation of metastatic orrecurrent disease or as initial treatment, in combination with surgeryand radiotherapy, for locally advanced disease.

Because squamous cell carcinoma of the head and neck is a heterogeneousdisease that can arise in multiple sites, the response rates to surgery,irradiation, and chemotherapy vary with the primary site of disease.Thus, prognosis is related not only to stage and histopathologicfeatures but also to site and, for patients who are undergoingchemotherapy, to prior treatment.

The strategy for treatment is determined by the stage of disease. Forearly disease, either surgery or radiotherapy can be employed becausethey give similar survival results. The choice depends on the expectedmorbidity from treatment (e.g., loss of speech or functionaldisfigurement from surgery or severe dryness of the mouth or alteredtaste from radiotherapy) as well as the urgency of treatment. With morelocally advanced disease, surgery and radiotherapy are combined becausethis approach produces improved control of local disease. Radiotherapymay be administered either preoperatively or postoperatively.Prophylactic radiotherapy is often administered for draining lymph nodesites, which are at high risk for microscopic involvement. Chemotherapyhas been incorporated into the initial treatment plan for patients withlocally advanced disease because five-year disease-free survival isgenerally low for such patients (10 to 30%) when conventional surgery,radiotherapy, or both are used.

There has been increasing concern that methods of treatment such assurgery, radiotherapy and chemotherapy may adversely affect thepatient's natural immunity which probably increases the chances ofgrowth of residual or metastatic tumor cells. This has directedattention not only to early detection and better treatment but also tomore research on the possible an etiology of the disease.

Research in the area of allergic reactions of the lung has providedevidence that arachidonic acid derivatives formed by the action oflipoxygenases are related to various disease states. Some of thesearachidonic acid metabolites have been classified as members of a familyof eicosatetraenoic acids termed leukotrienes. Three of these substancesare currently thought to be major components of what has been previouslycalled slow reacting substance of anaphylaxis (SRS-A) and have beendesignated leukotrienes C₄, D₄, and E₄ (LTC₄, LTD₄, and LTE₄,respectively).

Another arachidonic acid metabolite, leukotriene B₄ (LTB₄), is aproinflammatory lipid which has been implicated in the pathogenesis ofpsoriasis, arthritis, chronic lung diseases, acute respiratory distresssyndrome, shock, asthma, inflammatory bowel diseases, and otherinflammatory states characterized by the infiltration and activation ofpolymorphonuclear leukocytes and other proinflammatory cells. Thusactivated, the polymorphonuclear leukocytes liberate tissue-degradingenzymes and reactive chemicals causing the inflammation. Antagonism ofLTB₄ should therefore provide a novel therapeutic approach to treatmentof these and other LTB₄ mediated conditions.

Because of the debilitating effects of oral squamous cell carcinomathere continues to exist a need for effective treatments.

SUMMARY OF THE INVENTION

This invention provides a method for the treatment or inhibition of oralsquamous cell carcinoma which comprises administering to a mammal inneed thereof an effective amount of a compound of Formula I ##STR1##wherein: R₁ is C₁ -C₅ alkyl, C₂ -C₅ alkenyl C₂ -C₅ alkynyl, C₁ -C₄alkoxy, (C₁ -C₄ alkyl)thio, halo, or R₂ -substituted phenyl;

each R₂ and R₃ are each independently hydrogen, halo, hydroxy, C₁ -C₄alkyl, C₁ -C₄ alkoxy, (C₁ -C₄ alkyl)--S(O)_(q) --, trifluoromethyl, ordi-(C₁ -C₃ alkyl)amino;

X is --O--, --S--, --C(═O), or --CH₂ --;

Y is --O-- or --CH₂ --;

or when taken together, --X--Y-- is --CH═CH-- or

    --C.tbd.C--;

Z is a straight or branched chain C₁ -C₁₀ alkylidenyl;

A is a bond, --O--, --S--, --CH═CH--, or --CR_(a) R_(b) --, where R_(a)and R_(b) are each independently hydrogen, C₁ -C₅ alkyl, or R₇-substituted phenyl, or when taken together with the carbon atom towhich they are attached form a C₄ -C₈ cycloalkyl ring;

    R.sub.4 is R.sub.6 ##STR2## where, each R.sub.6 is independently --COOH, 5-tetrazolyl, --CON(R.sub.9).sub.2, or --CONHSO.sub.2 R.sub.10 ;

each R₇ is hydrogen, C₁ -C₄ alkyl, C₂ -C₅ alkenyl, C₂ -C₅ alkynyl,benzyl, methoxy, --W--R₆, --T--G--R₆, (C₁ -C₄ alkyl)--T--(C₁ -C₄alkylidenyl)--O--, or hydroxy;

R₈ is hydrogen or halo;

each R₉ is independently hydrogen, phenyl, or C₁ -C₄ alkyl, or whentaken together with the nitrogen atom form a morpholino, piperidino,piperazino, or pyrrolidino group;

R₁₀ is C₁ -C₄ alkyl or phenyl;

R₁₁ is R₂, --W--R₆, or --T--G--R₆ ;

each W is a bond or straight or branched chain divalent hydrocarbylradical of one to eight carbon atoms;

each G is a straight or branched chain divalent hydrocarbyl radical ofone to eight carbon atoms;

each T is a bond, --CH₂ --, --O--, --NH--, --NHCO--, --C(═O)--, or--S(O)_(q) --;

K is --C(═O)-- or --CH(OH)--;

each q is independently 0, 1, or 2;

p is 0 or 1; and

t is 0 or 1;

provided when X is --O-- or --S--, Y is not --O--;

provided when A is --O-- or --S--, R₄ is not R₆ ;

provided when A is --O-- or --S-- and Z is a bond, Y is not --O--; and

provided W is not a bond when p is 0;

or a pharmaceutically acceptable salt or solvate thereof.

DETAILED DESCRIPTION

The following definitions refer to the various terms used throughoutthis disclosure.

The term "C₁ -C₆ alkyl" refers to the straight and branched aliphaticradicals of 1 to 6 carbon atoms such as methyl, ethyl, propyl,isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, 2,2-dimethylpropyl,hexyl, and the like. Included within this definition are the terms "C₁-C₃ alkyl", "C₁ -C₄ alkyl" and "C₁ -C₅ alkyl".

The term "C₂ -C₅ alkenyl" refers to straight and branched aliphaticradicals of 2 to 5 carbon atoms containing one double bond, such as--CH═CH₂, --CH₂ CH═CH₂, --CH₂ CH₂ CH═CH₂, --CH₂ C(CH₃)═CH₂, --CH₂CH═C(CH₃)₂, and the like.

The term "C₂ -C₅ alkynyl" refers to straight and branched aliphaticresidues of 2 to 5 carbon atoms containing one triple bond, such as--C.tbd.CH, --CH₂ --C.tbd.--CH, --CH₂ CH₂ C.tbd.--CH, --CH₂CH(CH₃)C.tbd.--CH, --CH₂ C.tbd.CCH₃, and the like.

The term "C₁ -C₄ alkoxy" refers to methoxy, ethoxy, propoxy, isopropoxy,butoxy, sec-butoxy, and tert-butoxy.

The term "halo" refers to fluoro, chloro, bromo, and iodo.

The term or "C₁ -C₁₀ alkylidenyl" refers to a divalent radical derivedfrom a C₁ -C₁₀ alkane such as --CH₂ --, --CH(CH₃)--, --C(CH₃)₂ --,--CH(C₂ H₅)--, --CH₂ CH₂ --, --CH₂ CH(CH₃)--, --CH(CH₃)CH₂ --,--CH(CH₃)CH(CH₃)--, --CH₂ C(CH₃)₂ --, --CH₂ CH(C₂ H₅)--, --CH₂ CH₂ CH₂--, --CH(CH₃)CH₂ CH₂ --, --CH₂ CH(CH₃)CH₂ --, --CH₂ CH(C₂ H₅)CH₂ --,--CH₂ CH₂ CH(C₂ H₅)--, --C(CH₃)₂ CH₂ CH₂ --, --CH(CH₃)CH₂ CH(CH₃)--,--CH₂ CH₂ CH₂ CH₂ --, --CH₂ C(CH₃)₂ CH₂ CH₂ --, --CH₂ C(CH₃)₂ CH₂ --,--CH₂ CH₂ CH(C₂ H₅)CH₂ --, --CH₂ CH₂ CH₂ CH₂ CH₂ --, --CH(CH₃)CH₂ CH₂CH₂ CH₂ --, --CH₂ CH₂ CH₂ CH₂ CH₂ CH₂ --, --(CH₂)₁₀ --, and the like.Included within this definition are the terms "C₁ -C₄ alkylidene" and"C₂ -C₄ alkylidene".

The term "C₄ -C₈ cycloalkyl" refers to a cycloalkyl ring of four toeight carbon atoms, such as cyclobutyl, cyclopentyl, cyclohexyl,4,4-dimethylcyclohexyl, cycloheptyl, cyclooctyl, and the like.

The term "straight or branched chain divalent hydrocarbyl residue of oneto eight carbon atoms" refers to a divalent radical derived from astraight or branched alkane, alkene, or alkyne of one to eight carbonatoms. Depending upon the branching and number of carbon atoms, as willbe appreciated by organic chemists, such a moiety can contain one, twoor three double or triple bonds, or combinations of both. As such, thisterm can be considered an alkylidene group as defined above containingfrom 1 to 8 carbon atoms optionally containing one to three double ortriple bonds, or combinations of the two, limited as noted in thepreceding sentence.

This invention includes the pharmaceutically acceptable base additionsalts of the compounds of Formula I. Such salts include those derivedfrom inorganic bases, such as ammonium and alkali and alkaline earthmetal hydroxides, carbonates, bicarbonates, and the like, as well assalts derived from basic organic amines, such as aliphatic and aromaticamines, aliphatic diamines, hydroxy alkylamines, and the like. Suchbases useful in preparing the salts of this invention thus includeammonium hydroxide, potassium carbonate, sodium bicarbonate, calciumhydroxide, methyl amine, diethyl amine, ethylene diamine,cyclohexylamine, ethanolamine, and the like. The potassium and sodiumsalt forms are particularly preferred.

This invention includes both mono-salt forms, i.e., a 1:1 ratio of acompound of Formula I with a base as previously described, as well asdi-salt forms in those instances where a compound of Formula I has twoacidic groups. In addition, this invention includes any solvate forms ofthe compounds of Formula I or salts thereof, such as ethanol solvates,hydrates, and the like.

It is recognized that in compounds having branched alkyl, alkylidenyl,or hydrocarbyl functionality, and in those compounds bearing double ortriple bonds, various stereoisomeric products may exist. This inventionis not limited to any particular stereoisomer but includes all possibleindividual isomers and mixtures thereof. The term "5-tetrazolyl" refersto both tautomers, ie, (1H)-5-tetrazolyl and (2H)-5-tetrazolyl.

PREFERRED EMBODIMENTS

A most preferred group of compounds employed in the methods of thepresent invention are those compounds of Formula Ia: ##STR3## andpharmaceutically acceptable base addition salts thereof. Especiallypreferred are those compounds wherein R₂ is halo, particularly fluoro.Preferred R₁ substituents are propyl and especially ethyl.

Preferred Z substituents include C₂ -C₄ alkylidene, particularly --CH₂CH₂ -- and --CH₂ CH₂ CH₂ CH₂ --. Preferred A groups include --O--, --CH₂--, --CH(R₇ -substituted phenyl)--, and --(CH₃)₂ --.

Preferred R₄ groups include --COOH, 5-tetrazolyl, or a mono-, di-, ortri-cyclic group as drawn above wherein there is at least one acidicgroup attached to a ring, such as --W--COOH, --T--C--COOH, or thecorresponding tetrazole derivatives. The preferred W moiety is that of abond or straight chain C₁ -C₄ alkylidene; preferred G moieties arestraight chain C₁ -C₄ alkylidene. It is preferred that R₅ or R₇ be C₁-C₄ alkyl, especially n-propyl.

Particularly preferred groups are those wherein A is --CH(R₇-substituted phenyl)-- and R₄ is --COOH or 5-tetrazolyl. Also preferredare those compounds wherein A is --O-- and R₄ is ##STR4## Preferredaspects of this substructure are those wherein R₇ is C₁ -C₄ alkyl,especially n-propyl, and R₆ is --W--COOH. Particularly preferred arethose compounds wherein T is --O-- or --S-- and W is a bond.

Particularly preferred compounds of the instant invention include:

2- 2-propyl-3- 3-2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy!propoxy!phenoxy!benzoicacid;

3-(2-(3-(2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy)propoxy)-6-(4-carboxy-phenoxy)phenyl)propionicacid;

1-(4-(carboxy-methoxy)phenyl)-1-(1H-tetrazol-5-yl)-6-(2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy)hexane;

3- 4- 7-carboxy-9-oxo-3- 3-2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy!-propoxy!-9H-xanthene!!propanoicacid; and

5- 3- 2-(1-carboxy)-ethyl!-4- 3-2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy!-propoxy!phenyl!-4-pentynoicacid or a pharmaceutically acceptable salt or solvate thereof.

The leukotriene B₄ (LTB₄) antagonists employed in the methods of thepresent invention may be synthesized essentially as described in U.S.Pat. No. 5,462,954 issued Oct. 31, 1995, the entire contents of whichare herein incorporated by reference.

The following examples further illustrate the preparation of thecompounds employed in this invention. The examples are illustrative onlyand are not intended to limit the scope of the invention. Melting pointswere determined on a Thomas-Hoover apparatus and are uncorrected. NMRspectra were determined on a GE QE-300 spectrometer. All chemical shiftsare reported in parts per million (₋₋) relative to tetramethylsilane.Chemical shifts of aromatic protons of quinoline species in DMSO-d₆ areconcentration dependent. The following abbreviations are used to denotesignal patterns: s=singlet, d=doublet, t=triplet, q=quartet, b=broad,m=multiplet. Infrared spectra were determined on a Nicolet DX10 FT-IRspectrometer. Mass spectral data were determined on a CEC-21-110spectrometer using electron impact (EI) conditions, a MAT-731spectrometer using free desorption (FD) conditions, or a VG ZAB-3Fspectrometer using fast atom bombardment (FAB) conditions. Silica gelchromatography was performed using ethyl acetate/hexane gradients unlessotherwise indicated. Reverse-phase chromatography was performed on MCICHP20P gel using an acetonitrile/water or methanol/water gradient unlessotherwise indicated. Tetrahydrofuran (THF) was distilled fromsodium/benzophenone ketyl immediately prior to use. All reactions wereconducted under argon atmosphere with stirring unless otherwise noted.Where structures were confirmed by infra-red, proton nuclear magneticresonance, or mass spectral analysis, the compound is so designated by"IR", "NMR", or "MS", respectively.

EXAMPLE 1

3- 2- 3- (5-Ethyl-2-hydroxy1,1'-biphenyl!-4-yl)oxy!propoxy!-1-dibenzofuran!propanoic acid disodiumsalt ##STR5## A. Preparation of 3,3-diethoxy-2,3-dihydro-1H-benzofuro-3,2-f! 1!benzopyran

A solution of 2-hydroxydibenzofuran (5.00 g, 27.2 mmol),triethylorthoacrylate (10.1 g, 54.3 mmol) and pivalic acid (1.39 g, 13.6mmol) in toluene (100 mL) was refluxed for 18 hours. The mixture wascooled to room temperature and washed once with water and once with asaturated sodium bicarbonate solution, dried over sodium sulfate,filtered and concentrated in vacuo to provide an orange oil. Thismaterial was diluted with hexane and maintained at -20° C. for 18 hours.The resulting crystals were collected via vacuum filtration to provide5.67 g (67%) of the desired title intermediate, mp 64° C.; NMR (CDCl₃)7.96 (d, J=7.8 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.46 (t, J=8 Hz, 1H),7.35 (m, 2H), 7.06 (d, J=8.8 Hz, 1H), 3.82 (q, J=7.2 Hz, 2H), 3.73 (q,J=6.8 Hz, 2H), 3.35 (t, J=6.9 Hz, 2H), 2.29 (t, J=7.0 Hz, 2H), 1.23 (t,J=7.1 Hz, 6H); MS-FD m/e 312 (p); IR (CHCl₃, cm⁻¹) 2982, 1494, 1476,1451, 1434, 1251, 1090, 1054, 975.

Analysis for C₁₉ H₂₀ O₄ : Calc: C, 73.06; H, 6.45; Found: C, 72.81; H,6.72.

B. Preparation of 3- 1-(2-hydroxydibenzofuran)!propanoic acid ethylester

A mixture of 3,3-diethoxy-2,3-dihydro-1H-benzofuro- 3,2-f! 1!benzopyran(3.50 g, 11.2 mmol) and 10% aqueous hydrochloric acid (5 mL) in ethylacetate (30 mL) was stirred at room temperature for 1 hour. Theresulting mixture was washed once with water, dried over sodium sulfate,filtered and concentrated in vacuo to provide a tan solid.Recrystallization from hexane/ethyl acetate provided 3.11 g (98%) of thedesired title intermediate as an off-white crystalline material: mp128-131° C.; NMR (CDCl₃) 7.88 (d, J=7.7 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H),7.47 (t, J=7.2 Hz, 1H), 7.37 (d, J=8.9 Hz, 1H), 7.36 (t, J=6.6 Hz, 1H),7.13 (d, J=8.8 Hz, 1H), 7.13 (q, J=8.8 Hz, 2H), 3.43 (t, J=5.8 Hz, 2H),3.01 (t, J=7.7 Hz, 2H), 1.23 (t, J=7.2 Hz, 3H); MS-FD m/e 284 (100, p),256 (65), 238 (17); IR (KBr, cm-1) 2985 (b), 1701, 1430, 1226, 1183,1080.

Analysis for C₁₇ H₁₆ O₄ : Calc: C, 71.82; H, 5.67; Found: C, 71.90; H,5.43.

C. Preparation of 3- 2- 3- 5-ethyl-2-(phenylmethoxy)-1,1'-biphenyl!-4-yl!oxy!propoxy!-1-dibenzofuran!propanoic acid ethylester

3- 1-(2-Hydroxydibenzofuran)!propanoic acid ethyl ester (625 mg, 2.20mmol) was dissolved in dimethylformamide (10 mL) and carefully treatedat room temperature with 95% sodium hydride (58 mg, 2.4 mmol). When gasevolution had ceased,2-benzyloxy-1-phenyl-5-ethyl-4-(3-chloro-1-propyloxy)benzene (836 mg,2.20 mmol) was added and the resulting mixture was stirred for 18 hours.The mixture was diluted with ether and washed once with water. Theorganic layer was dried over sodium sulfate, filtered, and concentratedin vacuo to provide a dark oil. Silica gel chromatography (ethylacetate/hexane) provided 200 mg (14%) of the desired titled intermediateas a colorless oil: NMR (CDCl₃) 8.11 (d, J=7.7 Hz, 1H), 7.57 (m, 3H),7.48 (t, J=7.3 Hz, 1H), 7.20-7.44 (m, 10 H), 7.17 (s, 1H), 7.08 (d,J=8.9 Hz, 1H), 6.67 (s, 1H), 5.05 (s, 2H), 4.29 (t, J=6.2 Hz, 2H), 4.26(t, J=6.1 Hz, 2H), 4.15 (q, J=7.2 Hz, 2H), 3.54 (t, J=8.5 Hz, 2H), 2.67(m, 4H), 2.37 (t, J=6.0 Hz, 2H) , 1.21 (m, 6H).

D. Preparation of 3- 2- 3- (5-ethyl-2-hydroxy1,1'-biphenyl!-4-yl)oxy!propoxy!-1-dibenzofuran!propanoic acid disodiumsalt

To a nitrogen-purged solution of 3- 2- 3- 5-ethyl-2-(phenylmethoxy)1,1'-biphenyl!-4-yl!oxy!propoxy!-1-dibenzofuran!propanoic acid ethylester (200 mg, 0.318 mmol) in a 1:1 mixture of methanol/tetrahydrofuran(40 mL) was added 10% palladium on carbon (25 mg). The resultingsuspension was hydrogenated at 1 atm pressure for 24 hours at roomtemperature. The mixture was filtered through a short pad of Florisil®and the filtrate concentrated in vacuo. The residue was dissolved in a1:1 mixture of methanol/tetrahydrofuran (20 mL) and treated with 5 Nsodium hydroxide solution (2 mL) at room temperature for 24 hours. Theresulting mixture was extracted once with diethyl ether. The aqueouslayer was acidified with 5 N hydrochloric acid solution and extractedtwice with methylene chloride. The combined methylene chloride fractionswere concentrated in vacuo. The residue was dissolved in a minimum of 1N sodium hydroxide solution and purified on HP-20 resin to provide 53 mg(30%) of the desired title product as a fluffy white solid: NMR(DMSO-d₆) 8.12 (d, J=6.9 Hz, 1H), 7.64 (d, J=8.2 Hz, 1H), 7.37-7.57 (m,5H), 7.30 (m, 2H), 7.14 (m, 2H), 6.96 (s, 1H), 6.93 (s, 1H), 4.30 (t,J=7.3 Hz, 2H), 4.14 (t, J=5.4 Hz, 2H), 2.48 (m, 4H), 2.23 (m, 4H), 1.10(t, J=7.6 Hz, 3H); MS-FAB m/e 555 (88, p+1), 533 (62); IR (CHCl₃, cm⁻¹)3384 (b), 2969, 1566, 1428, 1257, 1181.

Analysis for C₃₂ H₂₈ O₆ Na₂ : Calc: C, 69.31; H, 5.09; Found: C, 69.51;H, 5.39.

EXAMPLE 2

7-Carboxy-9-oxo-3-3-(2-ethyl-5-hydroxy-4-phenylphenoxy)propoxy!-9H-xanthene-4-propanoicacid disodium salt monohydrate ##STR6##

A mixture of2-benzyloxy-1-phenyl-5-ethyl-4-(3-chloro-1-propyloxy)benzene (749 mg,1.97 mmol), ethyl 7-carboethoxy-3-hydroxy-9-oxo-9H-xanthene-4-propanoate(729 mg, 1.97 mmol), potassium carbonate (1.36 g, 9.85 mmol) andpotassium iodide (33 mg, 0.20 mmol) was refluxed for 24 hours.Dimethylsulfoxide (2 mL) was added and heating continued for 24 hours.The reaction mixture was cooled to room temperature, diluted with ethylacetate, and washed once with water. The organic layer was dried oversodium sulfate, filtered and concentrated in vacuo to reveal a tansolid. This material was dissolved in ethyl acetate (30 mL) and theresulting solution purged with nitrogen. To this solution was added 10%palladium on carbon (120 mg) and the resulting suspension hydrogenatedat 1 atmosphere of pressure. The solution was filtered and concentratedin vacuo to provide a colorless oil. This material was dissolved in asolution of 1:1 methanol/tetrahydrofuran (30 mL) and treated with 5 Nsodium hydroxide solution (2 mL) at room temperature for 18 hours. Theresulting solution was extracted once with diethyl ether and the aqueouslayer acidified with 5 N hydrochloric acid solution. The resultingprecipitate was collected via suction filtration. This material wasconverted to the di-sodium salt and purified as described above for thepreparation of Example 1(D) to provide 390 mg (56%) of the desired titleproduct as a fluffy white solid: NMR (DMSO-d₆) 12.65 (s, 1H, --OH), 8.65(s, 1H), 8.28 (dd, J=8.5, 2.0 Hz, 1H), 8.01 (d, J=8.9 Hz, 1H), 7.50 (m,3H), 7.29 (t, J=7.8 Hz, 2H), 7.17 (m, 2H), 6.93 (s, 1H), 6.89 (s, 1H),4.26 (m, 4H), 3.12 (m, 2H), 2.47 (m, 2H), 2.23 (m, 2H), 1.10 (t, J=7.4Hz, 3H); MS-FAB m/e 627 (24, p), 605 (40), 583 (24), 331 (24), 309(100); IR (KBr, cm⁻¹) 3419 (b), 2962, 1612, 1558, 1443, 1390, 1277,1084.

Analysis for C₃₄ H₂₈ O₉ Na₂.H₂ O: Calc: C, 63.34; H, 4.69; Found: C,63.36; H, 4.50.

EXAMPLE 3

2- 2-Propyl-3- 3-2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy!propoxy!phenoxy!benzoic acidsodium salt ##STR7## A. Preparation of 2- 2-propyl-3- 3-2-ethyl-4-(4-fluorophenyl)-5-(phenylmethoxy)phenoxy!propoxy!phenoxy!benzoicacid methyl ester

A mixture of2-benzyloxy-1-(4-fluorophenyl)-5-ethyl-4-(3-chloro-1-propyloxy)benzene(20.0 g, 50.2 mmol) and sodium iodide (75.3 g, 502 mmol) in 2-butanone(200 mL) was refluxed for 6 hours. The mixture was diluted with etherand washed once with water. The organic layer was dried over sodiumsulfate, filtered, and concentrated in vacuo to provide a colorless oil.This material was dissolved in dimethylformamide (100 mL) and treatedwith 2-(3-hydroxy-2-propylphenoxy)benzoic acid methyl ester (14.4 g,50.2 mmol) and potassium carbonate (20.8 g, 151 mmol) at roomtemperature for 24 hours. This mixture was diluted with water and twiceextracted with ether. The aqueous layer was separated and back-extractedonce with ethyl acetate. The combined organic layers were dried oversodium sulfate, filtered, and concentrated in vacuo to provide a yellowoil. Silica gel chromatography provided 25.4 g (78%) of the desiredtitle intermediate as a pale golden oil: NMR (CDCl₃) 7.91 (d, J=7.8 Hz,1H), 7.54 (d, J=8.6 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.25-7.43 (m, 6H),7.03-7.38 (m, 5H), 6.84 (d, J=8.3 Hz, 1H), 6.71 (d, J=8.1 Hz, 1H), 6.63(s, 1H), 6.47 (d, J=8.1 Hz, 1H), 5.03 (s, 2H), 4.24 (t, J=5.7 Hz, 2H),4.21 (t, J=5.8 Hz, 2H), 3.86 (s, 3H), 2.69 (t, J=7.8 Hz, 2H), 2.64 (t,J=7.7 Hz, 2H), 2.34 (quintet, J=6.0 Hz, 2H), 1.60 (hextet, J=5.0 Hz,2H), 1.22 (t, J=7.5 Hz, 3H), 0.94 (t, J=7.5 Hz, 3H); MS-FD m/e 648 (p);IR (CHCl₃, cm⁻¹) 2960, 1740, 1604, 1497, 1461, 1112.

Analysis for C₄₁ H₄₁ O₆ F: Calc: C, 75.91; H, 6.37; Found: C, 76.15; H,6.45.

B. Preparation of 2- 2-propyl-3- 3-2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy!propoxy!phenoxy!benzoic acidmethyl ester

2- 2-Propyl-3- 3-2-ethyl-4-(4-fluorophenyl)-5-(phenylmethoxy)phenoxy!propoxy!phenoxy!benzoicacid methyl ester (33.0 g, 50.9 mmol) was de-benzylated as describedabove for the preparation of Example 2 to provide 27.3 g (96%) of thetitle intermediate as an amber oil: NMR (CDCl₃) 7.90 (dd, J=7.8, 1.7 Hz,1H), 7.42 (m, 3H), 7.05-7.23 (m, 4H), 6.99 (s, 1H), 6.84 (d, J=8.1 Hz,1H), 6.70 (d, J=8.1 Hz, 1H), 6.55 (s, 1H), 6.46 (d, J=8.1 Hz, 1H), 5.05(s, 1H, --OH), 4.23 (m, 4H), 3.86 (s, 3H), 2.68 (t, J=7.4 Hz, 2H), 2.62(q, J=7.5 Hz, 2H), 2.36 (quintet, J=6.0 Hz, 2H), 1.60 (hextet, J=7.7 Hz,2H), 1.20 (t, J=7.6 Hz, 3H), 0.94 (t, J=7.4 Hz, 3H); MS-FD m/e 558 (p);IR (CHCl₃, cm⁻¹) 2965, 1727, 1603, 1496, 1458, 1306, 1112.

Analysis for C₃₄ H₃₅ O₆ F: Calc: C, 73.10; H, 6.31; Found: C, 73.17; H,6.42.

C. Preparation of 2- 2-propyl-3- 3-2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy!propoxy!phenoxy!benzoic acidsodium salt

2- 2-Propyl-3- 3-2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy!propoxy!phenoxy!benzoic acidmethyl ester (21.5 g, 38.5 mmol) was hydrolyzed as described above forthe preparation of Example 2. The acid was converted to the sodium saltand purified as described above for the preparation of Example 1(D) toprovide 16.7 g (77%) of the desired title product as a white amorphoussolid: NMR (DMSO-d₆) 10.50 (bs, 1H, --OH), 7.51 (m, 3H), 7.20 (t, J=7.4Hz, 1H), 7.13 (m, 2H), 7.00 (m, 2H), 6.95 (s, 1H), 6.67 (dd, J=8.2, 3.3Hz, 2H), 6.62 (s, 1H), 6.26 (d, J=8.2 Hz, 1H), 4.14 (t, J=5.8 Hz, 2H),4.02 (t, J=5.7 Hz, 2H), 2.60 (t, J=6.8 Hz, 2H), 2.47 (q, J=7.3 Hz, 2H),2.16 (t, J=5.9 Hz, 2H), 1.45 (hextet, J=7.5 Hz, 2H), 1.07 (t, J=7.5 Hz,3H), 0.81 (t, J=7.4 Hz, 3H); MS-FAB m/e 568 (38, p+1), 567 (100, p), 544(86), 527 (77), 295 (65), 253 (45); IR (KBr, cm⁻¹) 3407 (b), 2962, 1603,1502, 1446, 1395, 1239, 1112.

Analysis for C₃₃ H₃₂ O₆ FNa: Calc: C, 69.95; H, 5.69; F, 3.35; Found: C,69.97; H, 5.99; F, 3.52.

The methods of the present invention describe the use of leukotrieneantagonists for the treatment or prevention of oral squamous cellcarcinoma which is characterized by the excessive release of leukotrieneB₄.

The term "excessive release" of a leukotriene refers to an amount of theleukotriene sufficient to cause oral squamous cell carcinoma. The amountof leukotriene which is considered to be excessive will depend on avariety of factors, including the amount of leukotriene required tocause the disease, and the species of the mammal involved. As will beappreciated by those skilled in the art, the success of treating amammal suffering from or susceptible to oral squamous cell carcinomacharacterized by an excessive release of leukotriene with a compound ofFormula I will be measured by the regression or prevention of thesymptoms of the condition.

ASSAYS

Assay 1

The effectiveness of compounds of Formula I to inhibit the binding oftritiated LTB₄ to guinea pig lung membranes was determined as follows.

³ H!-LTB₄ Radioligand Binding Assay in Guinea Pig Lung Membranes

³ H!-LTB₄ (196-200 Ci/mmole) was purchased from New England Nuclear(Boston, Mass.). All other materials were purchased from Sigma (St.Louis, Mo.). Incubations (555 mL) were performed in polypropyleneminitubes for 45 minutes at 30° C. and contained 25 mg of guinea piglung membrane protein (Silbaugh, et al., European Journal ofPharmacology, 223 (1992) 57-64) in a buffer containing 25 mM MOPS, 10 mMMgCl₂, 10 mM CaCl₂, pH 6.5, approximately 140 pM ³ H!-LTB₄, anddisplacing ligand or vehicle (0.1% DMSO in 1 mM sodium carbonate, finalconcentration) as appropriate. The binding reaction was terminated bythe addition of 1 mL ice cold wash buffer (25 mM Tris-HCl, pH 7.5)followed immediately by vacuum filtration over Whatman GF/C glass fiberfilters using a Brandel (Gaithersburg, Md.) 48 place harvester. Thefilters were washed three times with 1 mL of wash buffer. Retainedradioactivity was determined by liquid scintillation counting at 50%counting efficiency using Ready Protein Plus cocktail (Beckman,Fullerton, Calif.). Nondisplaceable binding was determined in thepresence of 1 mM LTB₄ and was usually less than 10% of total binding.Data were analyzed using linear regression analysis of log-logit plotsof the values between 10% and 90% of control binding to calculate IC₅₀ sand slope factors (pseudo-Hill coefficients). IC₅₀ values thus obtainedwere corrected for radioligand concentration (Cheng and Prusoff,Biochem. Pharmacol., 22, 3099 (1973)) to calculate K_(i) values. pKi isthe mean-log K_(i) for n experiments.

Compounds of the instant invention tested in the above assay were foundto have a pKi of between 7 and 11.

The ability of a compound of formula I to effectively treat experimentaloral cancer can be evaluated by testing its effect on induction ofsquamous cell carcinoma in the cheek pouch of Syrian hamsters (Polliack,et al., Br.J.Cancer 23, 781-6, 1969).

Assay 2

Tumor development is induced by painting the right cheek pouches ofSyrian hamsters (1.5 to 2 months of age) with 0.5% solution of9,10-dimethyl-1,2-benzanthracene (DMBA) in heavy mineral oil (USP) threetimes per week for 15 weeks. At the completion of the above treatment,the animals are killed, autopsies are performed and both cheek pouchesexamined for the number and size of tumors. The nature of the lesionsare subsequently determined histologically after fixing the tissue in 4%formalin and staining with haematoxylin and eosin. A dose response isobtained by dividing the animals into 4 experimental groups of 10hamsters each. The groups are: vehicle-treated; 10, 25, and 50 mg/kg/dayof a compound of formula I administered orally to the animals. Theeffectiveness of a treatment is accessed by comparing the size andnumber of squamous cell carcinomas and the number of atypical papillomasof the treated group to that of the vehicle control.

Assay 3

Clinical Studies: Human clinical trials may also be employed to assessthe value of the compounds of Formula I in treating oral squamous cellcarcinoma. The design of clinical trials, use of assessment instruments,and interpretation of these results are well known to clinicians in thefield. For example: Five to fifty patients are selected for the clinicalstudy. The patients suffer from squamous cell carcinoma. The study has aplacebo control group, i.e., the patients are divided into two groups,one of which receives a compound of formula I as the active agent andthe other receives a standard treatment for squamous cell carcinoma.Patients in the test group receive between 30-1500 mg of the drug perday by the oral or parenteral route. They continue this therapy for 3-12months. Accurate records are kept as to the symptoms and status of thecancer in both groups and at the end of the study these results arecompared. The results are compared both between members of each groupand also the results for each patient are compared to the statusreported for each patient before the study began.

The therapeutic and prophylactic treatments provided by this inventionare practiced by administering to a mammal in need thereof a dose of acompound of formula I or a pharmaceutically acceptable salt or solvatethereof, that is effective to inhibit or treat oral squamous cellcarcinoma.

The term "inhibit" includes its generally accepted meaning whichincludes prohibiting, preventing, restraining and slowing, stopping orreversing progression, severity or a resultant symptom. As such, thepresent method includes both medical therapeutic and/or prophylacticadministration as appropriate.

While it is possible to administer a compound employed in the methods ofthis invention directly without any formulation, the compounds areusually administered in the form of pharmaceutical formulationcomprising a pharmaceutically acceptable excipient and at least onecompound of the present invention. The compounds or formulations of thepresent invention may be administered by the oral and rectal routes,topically, parenterally, e.g., by injection and by continuous ordiscontinuous intra-arterial infusion, in the form of, for example,tablets, lozenges, sublingual tablets, sachets, cachets, elixirs, gels,suspensions, aerosols, ointments, for example, containing from 0.01 to90% by weight of the active compound in a suitable base, soft and hardgelatin capsules, suppositories, injectable solutions and suspensions inphysiologically acceptable media, and sterile packaged powders adsorbedonto a support material for making injectable solutions. Suchformulations are prepared in a manner well known in the pharmaceuticalart and comprise at least one active compound. See, e.g., REMINGTON'sPHARMACEUTICAL SCIENCES, (16th ed. 1980).

In making the formulations employed in the present invention the activeingredient is usually mixed with an excipient, diluted by an excipientor enclosed within such a carrier which can be in the form of a capsule,sachet, paper or other container. When the excipient serves as adiluent, it can be a solid, semi-solid, or liquid material, which actsas a vehicle, carrier or medium for the active ingredient. In preparinga formulation, it may be necessary to mill the active compound toprovide the appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, itordinarily is milled to a particle size of less than 200 mesh. If theactive compound is substantially water soluble, the particle size isnormally adjusted by milling to provide a substantially uniformdistribution in the formulation, e.g. about 40 mesh.

Some examples of suitable carriers, excipients and diluents includelactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia,calcium phosphate, alginates, tragacanth, gelatin, calcium silicate,microcrystalline cellulose, polyvinylpyrrolidone, cellulose, tragacanth,gelatin, water, syrup, and methyl cellulose. The formulations canadditionally include: lubricating agents such as talc, magnesiumstearate, and mineral oil; wetting agents; emulsifying and suspendingagents; preserving agents such as methyl- and propylhydroxybenzoates;sweetening agents; and flavoring agents. The compositions of theinvention can be formulated so as to provide quick, sustained or delayedrelease of the active ingredient after administration to the patient byemploying procedures known in the art.

The compounds of this invention may be delivered transdermally usingknown transdermal delivery systems and excipients. Most preferably, acompound of this invention is admixed with permeation enhancersincluding, but not limited to, propylene glycol, polyethylene glycolmonolaurate, and azacycloalkan-2-ones, and incorporated into a patch orsimilar delivery system. Additional excipients including gelling agents,emulsifiers, and buffers may be added to the transdermal formulation asdesired.

For topical administration, a compound of this invention ideally can beadmixed with any variety of excipients in order to form a viscous liquidor cream-like preparation.

For oral administration, a compound of this invention ideally can beadmixed with carriers and diluents and molded into tablets or enclosedin gelatin capsules.

In the case of tablets, a lubricant may be incorporated to preventsticking and binding of the powdered ingredients in the dies and on thepunch of the tableting machine. For such purpose there may be employedfor instance aluminum, magnesium or calcium stearates, talc or mineraloil.

Preferred pharmaceutical forms of the present invention includecapsules, tablets and injectable solutions. Especially preferred arecapsules and tablets.

The therapeutic and prophylactic treatments provided by this inventionare practiced by administering to a mammal in need thereof a dose of acompound of formula I or a pharmaceutically acceptable salt or solvatethereof that is effective to inhibit or treat oral squamous cellcarcinoma.

Advantageously for this purpose, formulations may be provided in unitdosage form, preferably each dosage unit containing from about 5 toabout 500 mg (from about 5 to 50 mg in the case of parenteral orinhalation administration, and from about 25 to 500 mg in the case oforal or rectal administration) of a compound of Formula I. Dosages fromabout 0.5 to about 300 mg/kg per day, preferably 0.5 to 20 mg/kg, ofactive ingredient may be administered although it will, of course,readily be understood that the amount of the compound or compounds ofFormula I actually to be administered will be determined by a physician,in the light of all the relevant circumstances including the conditionto be treated, the choice of compound to be administered and the choiceof route of administration and therefore the above preferred dosagerange is not intended to limit the scope of the present invention in anyway.

The specific dose of a compound administered according to this inventionto obtain therapeutic or prophylactic effects will, of course, bedetermined by the particular circumstances surrounding the case,including, for example, the route of administration the age, weight andresponse of the individual patient, the condition being treated and theseverity of the patient's symptoms.

In general, the compounds of the invention are most desirablyadministered at a concentration that will generally afford effectiveresults without causing any serious side effects and can be administeredeither as a single unit dose, or if desired, the dosage may be dividedinto convenient subunits administered at suitable times throughout theday.

While all of the compounds illustrated above exemplify LTB₄ inhibitionactivity in vitro, we have also discovered that compounds bearing asingle acidic group (R₆) are considerably more orally bioactive whenadministered to mammals compared with those compounds bearing two suchacidic groups. Thus, a preferred embodiment when administering compoundsof Formula I orally to mammals comprises administering compounds bearinga single acidic R₆ functionality.

The following formulation examples may employ as active compounds any ofthe compounds of this invention. The examples are illustrative only andare not intended to limit the scope of the invention in any way.

Formulation 1

Hard gelatin capsules are prepared using the following ingredients:

    ______________________________________                       Quantity (mg/capsule)    ______________________________________    3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5-                         250    hydroxyphenoxy)propoxy)-6-(4-carboxy-    phenoxy)phenyl)propanoic acid    Starch               200    Magnesium stearate    10    ______________________________________

The above ingredients are mixed and filled into hard gelatin capsules in460 mg quantities.

Formulation 2

A tablet is prepared using the ingredients below:

    ______________________________________                        Quantity (mg/tablet)    ______________________________________    1-(4-(Carboxymethoxy)phenyl)-1-(1H-                          250    tetrazol-5-yl)-6-(2-ethyl-4-(4-    fluorophenyl)-5-hydroxyphenoxy)hexane    Cellulose, microcrystalline                          400    Silicon dioxide, fumed                           10    Magnesium stearate     5    ______________________________________

The components are blended and compressed to form tablets each weighing665 mg.

Formulation 3

An aerosol solution is prepared containing the following components:

    ______________________________________                          Weight %    ______________________________________    3- 4- 7-Carboxy-9-oxo-3- 3- 2-ethyl-4-                             0.25    (4-fluorophenyl)-5-hydroxyphenoxy!propoxy!-    9H-xanthene!!propanoic acid    Ethanol                 30.00    Propellant 11           10.25    (trichlorofluoromethane)    Propellant 12           29.75    (Dichlorodifluoromethane)    Propellant 114          29.75    (Dichlorotetrafluoroethane)    ______________________________________

The active compound is dissolved in the ethanol and the solution isadded to the propellant 11, cooled to -30° C. and transferred to afilling device. The required amount is then fed to a container andfurther filled with the pre-mixed propellants 12 and 114 by means of thecold-filled method or pressure-filled method. The valve units are thenfitted to the container.

Formulation 4

Tablets each containing 60 mg of active ingredient are made up asfollows:

    ______________________________________    2- 2-Propyl-3- 3- 2-ethyl-5-hydroxy-4-(4-                          60 mg    fluorophenyl)phenoxy!propoxy!phenoxy!-    benzoic acid sodium salt    Starch                45 mg    Microcrystalline cellulose                          35 mg    Polyvinylpyrrolidone   4 mg    (as 10% solution in water)    Sodium carboxymethyl starch                          4.5 mg    Magnesium stearate    0.5 mg    Talc                   1 mg    Total                 150 mg    ______________________________________

The active ingredient, starch and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granules so produced aredried at 50-60° and passed through a No. 18 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate and talc, previously passedthrough a No. 60 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 150 mg.

Formulation 5

Capsules each containing 80 mg of medicament are made as follows:

    ______________________________________    5- 3- 2-(1-Carboxy)ethyl!-4- 3- 2-ethyl-4-(4-                            80 mg    fluorophenyl)-5-hydroxyphenoxy!propoxy!-    phenyl!-4-pentynoic acid    Starch                  59 mg    Microcrystalline cellulose                            59 mg    Magnesium stearate       2 mg    Total                   200 mg    ______________________________________

The active ingredient, cellulose, starch and magnesium stearate areblended, passed through a No. 45 mesh U.S. sieve, and filled into hardgelatin capsules in 200 mg quantities.

Formulation 6

Suppositories each containing 225 mg of active ingredient are made asfollows:

    ______________________________________    3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5-                            225 mg    hydroxyphenoxy)propoxy)-6-(4-carboxy-    phenoxy)phenyl)propanoic acid    Unsaturated or saturated fatty                          2,000 mg    acid glycerides to    ______________________________________

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the fatty acid glycerides previously melted using theminimum heat necessary. The mixture is then poured into a suppositorymold of nominal 2 g capacity and allowed to cool.

Formulation 7

Suspensions each containing 50 mg of medicament per 5 mL dose are madeas follows:

    ______________________________________    2- 2-Propyl-3- 3- 2-ethyl-4-(4-fluorophenyl)-                              50 mg    5-hydroxyphenoxy!propoxy!phenoxy!benzoic    acid    Sodium carboxymethyl cellulose                              50 mg    Sugar                     1 g    Methyl paraben          0.05 mg    Propyl paraben          0.03 mg    Flavor                  q.v.    Color                   q.v.    Purified water to         5 mL    ______________________________________

The medicament is passed through a No. 45 mesh U.S. sieve and mixed withthe sodium carboxymethylcellulose, sugar, and a portion of the water toform a suspension. The parabens, flavor and color are dissolved anddiluted with some of the water and added, with stirring. Sufficientwater is then added to produce the required volume.

Formulation 8

An intravenous formulation may be prepared as follows:

    ______________________________________    2- 2-propyl-3- 3- 2-ethyl-4-(4-                             100 mg    fluorophenyl)-5-    hydroxyphenoxy!propoxy!phenoxy!benzoic    acid    Isotonic saline        1,000 ml    ______________________________________

The solution of the above ingredients generally is administeredintravenously to a subject at a rate of 1 ml per minute.

We claim:
 1. A method for treating oral squamous cell carcinoma in amammal which comprises administering to a mammal in need thereof aneffective amount of a compound of the formula ##STR8## wherein: R₁ is C₁-C₅ alkyl, C₂ -C₅ alkenyl, C₂ -C₅ alkynyl, C₁ -C₄ alkoxy, (C₁ -C₄alkyl)thio, halo, or R₂ -substitutedphenyl;each R₂ and R₃ are eachindependently hydrogen, halo, hydroxy, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, (C₁-C₄ alkyl)--S(O)_(q) --, trifluoromethyl, or di-(C₁ -C₃ alkyl)amino; Xis --O--, --S--, --C(═O), or --CH₂ --; Y is --O-- or --CH₂ --; or whentaken together, --X--Y-- is --CH═CH-- or

    --C.tbd.C--;

Z is a straight or branched chain C₁ -C₁₀ alkylidenyl; A is a bond,--O--, --S--, --CH═CH--, or --CR_(a) R_(b) --, where R_(a) and R_(b) areeach independently hydrogen, C₁ -C₅ alkyl, or R₇ -substituted phenyl, orwhen taken together with the carbon atom to which they are attached forma C₄ -C₈ cycloalkyl ring; ##STR9## where, each R₆ is independently--COOH, 5-tetrazolyl, --CON(R₉)₂, or --CONHSO₂ R₁₀ ; each R₇ ishydrogen, C₁ -C₄ alkyl, C₂ -C₅ alkenyl, C₂ -C₅ alkynyl, benzyl, methoxy,--W--R₆, --T--G--R₆, (C₁ -C₄ alkyl)--T--(C₁ -C₄ alkylidenyl)--O--, orhydroxy; R₈ is hydrogen or halo; each R₉ is independently hydrogen,phenyl, or C₁ -C₄ alkyl, or when taken together with the nitrogen atomform a morpholino, piperidino, piperazino, or pyrrolidino group; R₁₀ isC₁ -C₄ alkyl or phenyl; R₁₁ is R₂, --W--R₆, or --T--G--R₆ ; each W is abond or straight or branched chain divalent hydrocarbyl radical of oneto eight carbon atoms; each G is a straight or branched chain divalenthydrocarbyl radical of one to eight carbon atoms; each T is a bond,--CH₂ --, --O--, --NH--, --NHCO--, --C(═O)--, or --S(O)_(q) --; K is--C(═O)-- or --CH(OH)--; each q is independently 0, 1, or 2; p is 0 or1; and t is 0 or 1; provided when X is --O-- or --S--, Y is not --O--;provided when A is --O-- or --S--, R₄ is not R₆ ; provided when A is--O-- or --S-- and Z is a bond, Y is not --O--; and provided W is not abond when p is 0;or a pharmaceutically acceptable salt or solvatethereof.
 2. The method as claimed in claim 1 employing a compound of theformula ##STR10## or a pharmaceutically acceptable salt or solvatethereof.
 3. The method as claimed in claim 2 employing 2- 2-propyl-3- 3-2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy!propoxy!phenoxy!benzoic acidor a pharmaceutically acceptable salt or solvate thereof.
 4. The methodas claimed in claim 2 employing3-(2-(3-(2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy)propoxy)-6-(4-carboxy-phenoxy)phenyl)propionicacid or a pharmaceutically acceptable salt or solvate thereof.
 5. Themethod as claimed in claim 2 employing1-(4-(carboxy-methoxy)phenyl)-1-(1H-tetrazol-5-yl)-6-(2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy)hexaneor a pharmaceutically acceptable salt or solvate thereof.
 6. The methodas claimed in claim 2 employing 3- 4- 7-carboxy-9-oxo-3- 3-2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy!-propoxy!-9H-xanthene!!propanoicacid or a pharmaceutically acceptable salt or solvate thereof.
 7. Themethod as claimed in claim 2 employing 5- 3- 2-(1-carboxy)-ethyl!-4- 3-2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy!-propoxy!phenyl!-4-pentynoicacid or a pharmaceutically acceptable salt or solvate thereof.
 8. Themethod as claimed in claim 1 in which the mammal is a human.
 9. Themethod as claimed in claim 2 in which the mammal is a human.
 10. Themethod as claimed in claim 3 in which the mammal is a human.
 11. Themethod as claimed in claim 4 in which the mammal is a human.
 12. Themethod as claimed in claim 5 in which the mammal is a human.
 13. Themethod as claimed in claim 6 in which the mammal is a human.
 14. Themethod as claimed in claim 7 in which the mammal is a human.